Bovine herpesvirus type 1 is an economically significant pathogen of cattle. BHV-1, which is also known as infectious bovine rhinotracheitis virus, causes severe respiratory infections, conjunctivitis, vulvovaginitis, abortions, encephalitis, and generalized systemic infections. If an animal recovers from a primary infection, the virus remains in the host in a latent state. Reactivation of the virus can be provoked by certain endogenous or exogenous physical modifications in the animal, or experimentally by treatment of the animal with glucocorticoids such as dexamethasone.
In an effort to control BHV-1 infections, conventional killed-virus and attenuated live-virus vaccines have been developed. Current modified live virus vaccines may cause immunosuppression. No recombinant forms of BHV-1, specifically attenuated by genetic engineering are currently licensed for use is cattle. While currently available vaccines appear to induce some level of protection in cattle, the level of immunity is well below that necessary to afford complete or near-complete protection. For example, the present vaccines do not always prevent the establishment of a latent infection by a virulent field strain of BHV-1. See, e.g., Gerber et al. (1978) Am. J. Vet. Res. 39:753-760; Jericho et al. (1983) Can. J. Com. Med. 47:133-139; Pastoret et al. (1980) Infect. Immun. 29:483-488.
Babiuk et al. (1987) Virology 159:57-66 relates to the purification of gI, gIII and gIV from virus-infected cell lysates, effective subunit vaccines and the protection of cattle from disease. This reference also discloses that gI of BHV-1 corresponds to gB of herpes simplex virus (HSV); gIII corresponds to gC; and gIV corresponds to gD. Purified gI, gIII and gIV have been shown to induce high levels of antibody in cattle which could neutralize virus and participate in antibody-dependent cell cytotoxicity of BHV-1 cells. The purified glycoproteins were also shown to protect cattle from disease. Babiuk et al. (1987) Virology 159:57-66. van Drunen Littel-van den Hurk et al. (1990) Vaccine 8:358-368 confirmed the protectivity of gI, gIII and gIV and studied the epitope specificity of the immune response to the glycoprotein vaccines. Hughes et al. (1988) Arch. Virol. 103:47-60 identified three neutralizing antigenic domains on gIV.
Mayfield et al. (1983) J. Virol. 47:259-264 discloses the cloning of a BHV-1 strain and a restriction endonuclease map. Fitzpatrick et al. (1989) Virology 173:46-57, describe the nucleotide sequence of gIII. Pachl et al. (1987) J. Virol. 61:315-325 describe the recombinant expression of a glycoprotein from the human pathogen HSV-1. van Drunen Littel-van den Hurk et al. (1989) J. Virol. 63:2159-2168 disclose the expression of gI and GIII in a vaccinia virus vector. The recombinant vectors elicited a neutralizing antibody response in cattle immunized with the same.
Liang et al. (1991a) J. Virol. 65(3):1124-1132 report that BHV-1 attachment to permissive cells is mediated by its major glycoproteins gI, gIII and gIV, and Liang et al. (1991b) J. Virol. 65(10):5553-5557 report that pseudorabies virus gIII and BHV-1 gIII share complementary functions.
Liang et al. (1992) Virol. 189:629-639 describe a glycoprotein gIII.sup.- BHV-1 mutant expressing .beta.-galactosidase, the role of gIII in virus infectivity and its use as a vector for mucosal immunization.
Kit et al. (1991) Vaccine, 9:564-572 report the expression of foot and mouth disease epitopes via a BHV-1 gIII.sup.- based viral vector in which the signal sequence was deleted. Lawrence et al. (1990) Abstracts of the 15th International Herpes Virus Workshop, p. 432, disclose a BHV-1 recombinant expressed vesicular stomatitis virus glycoprotein G which is not transported to the cell surface.
Pyles et al. (1990) Abstracts of the 15th International Herpes Virus Workshop, p. 164, disclose the role of deoxyuridine triphosphatase in HSV-1 pathogenesis. McGeoch et al. (1990) Nucl. Acid Res. 18(14):4105-4109 report protein sequence comparisons which show that pseudoproteases encoded by poxviruses and certain retroviruses belong to the deoxyuridine triphosphatase family.
van Zijl et al. (1991) J. Virol. 65(5):2761-2765 describe the expression of hog cholera virus envelope glycoprotein E1 by an attenuated live pseudorabies virus which afforded swine protection against both pseudorabies and hog cholera.
Cattle are subject to numerous other viral, bacterial, fungal, and parasitic infections of the respiratory, enteric, and genital tracts (Babiuk et al. (1988) Adv. Virus Res., 35:219-249) for which vaccines either do not exist or do not adequately protect against infection. A common characteristic of non-protective vaccines is their failure to stimulate the development of mucosal immunity. The lack of stimulation may be due to a failure to specifically direct antigens towards the functionally- and anatomically-distinct "common mucosal immune system" (Husband, A. J. (1987) Vet Immunol. Immunopathol., 17:357-365) and/or the use of inappropriate adjuvants which fail to specifically stimulate cells of the common mucosal immune system.
Karupiah et al. (November 1990) J. Exp. Med. 172:1495-1503 report that gamma-interferon is involved in the recovery of athymic nude mice from treatment with recombinant vaccinia virus encoding murine interleukin-2 (IL-2). Ramshaw et al. (1987) Nature 329:545-546 disclose the recovery of immunodeficient mice from the same treatment. Flexner et al. (1987) Nature 330:259-262 disclose the prevention of vaccinia virus infection in immunodeficient mice by vector-directed IL-2 expression. Giavendon et al. (1992) Proc. Natl. Acad. Sci. USA 89:3409-3413 report that vaccinia virus recombinants that express chimeric proteins comprising human immunodeficiency virus peptide and gamma-interferon are attenuated for nude mice.
Sambhi et al. (1991) Proc. Natl. Acad. Sci. USA 88:4025-4029 report that the local production of tumor necrosis factor encoded by recombinant vaccinia virus is effective in controlling viral replication in vivo.
A new generation of natural adjuvants have been developed by cloning and expression of the endogenous cytokines which normally regulate the immune responses of cattle. It has been shown that several of these compounds, when administered in combination with vaccines, may have immuno-stimulating activity. No reports have yet described their possible effects on the common mucosal immune system of cattle. Moreover, there have been no reports that describe engineering of recombinant bovine viruses to produce immunomodulatory cytokines during the natural course of an infection with such a recombinant virus.